Is TSC2 p.Ala889Val (c.2666C>T) pathogenic?

TSC2 p.Ala889Val (c.2666C>T) is classified Pathogenic/Likely pathogenic in TSC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9948); Absent from gnomAD v4.1; Associated with TSC2-related disorder.

What condition is associated with TSC2 p.Ala889Val (c.2666C>T)?

TSC2 p.Ala889Val (c.2666C>T) is associated with TSC2-related disorder, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ala889Val (c.2666C>T) in the general population?

TSC2 p.Ala889Val (c.2666C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Ala889Val (c.2666C>T)?

AlphaMissense predicts likely pathogenic (score 0.9948) — an in-silico prediction, not a clinical call.

TSC2 p.Ala889Val

c.2666C>T · rs137854155 · VCV49586

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9948 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TSC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9948	likely pathogenic ✓ concordant with ClinVar · top 3% in TSC2
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -13.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC2
Protein: p.Ala889Val
Coding: c.2666C>T
MANE Select: NM_000548
dbSNP: rs137854155
Type: single nucleotide variant
Location: chr16:2076094 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 889: an α-helix

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TSC2-related disorder

Also linked: tuberous sclerosis tuberous sclerosis 2 hereditary neoplastic syndrome

Similar variants

TSC2 p.Ala889Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala889Pro Likely pathogenic ★ same residue
TSC2 p.Ala889Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Ala889= Benign ★ same residue
TSC2 p.Ala889fs Pathogenic ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G Pathogenic ★★ same condition
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tsc2-p-ala889val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown